N-(2-Aminocyclopentyl) alkanoylanilides

ABSTRACT

N-(2-Aminocyclopentyl)N-alkanoylanilides and their 2-N-oxides of the formula ##STR1## e.g., trans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide, and their pharmacologically acceptable salts, have been found to possess potent Central Nervous System anti-depressant properties. Many of them are new. 
     These compounds are promising anti-depressant drugs which are characterized by a better therapeutic ratio than imipramine, and long acting activity which may allow longer durations between administrations, e.g., once a day. Pharmaceutical compositions containing these compounds and a process for treating conditions of depression with these compositions are disclosed.

This application is a division of U.S. Pat. application Ser. No. 777,599filed Mar. 15, 1977, which is a continuation-in-part of U.S. Pat.application Ser. No. 746,191, filed Nov. 30, 1976.

INTRODUCTION

This invention relates to amino-cycloaliphatic amides which have centralnervous system pharmaceutical utility. More particularly this inventionprovides some new pharmaceutical preparations containing cis and transN-(2-aminocyclopentyl)-N-alkanoylanilide compounds or theirpharmacologically acceptable salts which have been found to have potentcentral nervous system (CNS) antidepressant properties which makes themuseful as antidepressant drugs, when formulated into usefulpharmaceutically useable composition forms, and administered inappropriate dosages.

BACKGROUND OF THE INVENTION

W. G. Stoll et al., in Helvetica Chemica Acta, Vol. 34, (1951), pp. 1937to 1943 disclose N-[2-(dimethylamino)-cyclohexyl]aniline and proceduresfor making it from N-(2-hydroxycyclohexyl)aniline and suggest that thecompounds therein have antihistamine pharmacological properties, butnothing is said about the compounds of this invention or their use asantidepressant drugs.

J. W. Lewis et al., in an article entitled "The Reactions of AromaticNitroso-compounds with Enamines. Part I. The Reaction of Nitrosobenzenewith 1-Morpholin-1-cyclohexene" in J. Chem. Soc. (London) (1972),Perkins Transactions I, Part III, pp. 2521-2524 discloses inter aliaN-(2morpholin-1-ylcyclohexyl)phenylhydroxylamine and its hydrochloridesalt, but it does not disclose or suggest the alkanoyl-anilides of thisinvention or their antidepressant properties.

J. W. Lewis et al., in an article entitled "Chemistry and BiologicalActivity of N-Substituted Hydroxylamines" in J. Pharmaceutical Sciences,December, 1974, Vol. 63, No. 12, pp. 1951-1953 discloses someN-Arylhydroxylamines such asN-[2-(N-pyrrolidinyl)cyclohexyl]-N-phenylhydroxylamine but these do nothave useful CNS properties. Diuretic activity is alleged therein for thealcohols such as [2-(N-piperidinylcyclohexyl]-(4-methoxyphenyl)methanoland when the alcohol is acetylated CNS depressant activity is said toappear. It also discloses the reaction of propionyl chloride withN-[2-(N-piperidinyl)-1,1-dimethylethyl]-N-phenylhydroxylamine to formthe N-chloro compound which is then converted to a mixture ofchlorinated aniline derivatives. That publication does not teach thecompounds disclosed herein, how to make them, nor does it suggest theantidepressant properties which have been found for the compoundsdisclosed and claimed herein.

Szmuszkovicz U.S. Pat. No. 3,510,492 discloses and claims some2-anilino- and 2-anilinomethylcycloalkylamines which are useful asantidiabetic drugs in that they can be administered in low dosages forreducing blood sugar. However, that patent in column 2, structure IVgenerically suggests some of the formula I compounds of thepharmaceutical preparations and use process of this invention aschemical intermediates en route to the 2-anilinocycloalkyl aminesthereof, but it does not suggest any end product practical utility forthose structure IV compounds.

OBJECTS OF THE INVENTION

It is an object of this invention to provide some newN-(2-aminocyclopentyl)alkanoylanilides which have been found to havepromising antidepressant drug properties.

It is a more specific object of this invention to provide newN-(2-aminocyclopentyl)alkanoylanilides which are useful asantidepressant drugs the preferred compounds having a better therapeuticratio than imipramine and longer lasting activity which allows longerdurations between administrations.

It is another object of this invention to provide compositions, usefulin pharmaceutical dosage unit form, for treating conditions ofdepression in mammals including humans comprising anN-(2-aminocyclopentyl)alkanoylanilides as described herein, or apharmacologically acceptable salt thereof in a pharmaceutical carrier.

It is another object of this invention to provide a process for treatingconditions of depression in mammals including humans with thesecompositions containing an N-(2-aminocyclopentyl)alkanoylanilide, or apharmacologically acceptable salt thereof.

Other objects, aspects and advantages of this invention will be apparentfrom reading the specification and claims which follow.

SUMMARY OF THE INVENTION

Briefly, this invention provides pharmaceutical preparations of some cisand trans-N-(2-aminocyclopentyl)N-alkanoylanilides of the formula##STR2## and their pharmacologically acceptable salts, wherein p, Q, R,R₁, R₂, Y and Z are as defined hereinbelow, which have been found topossess potent central nervous system (CNS) antidepressant properties. Apreferred example for this use istrans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide. Thisinvention also includes these compounds (I) which are new, per se, andtheir acid addition salts, especially their pharmacologically acceptablesalts. These compounds are useful, in appropriate pharmaceutical dosageunit form, for administration of humans in dosages of from 1-100 mg. perday as part of the therapy in treating conditions of depression. Instandard laboratory animals used to determine these properties thesecompounds suggest fast onset of the antidepressant characteristics ofthe drug, the preferred compounds having in addition, a bettertherapeutic ratio (higher activity and/or lower toxicity) than astandard antidepressant drug, imipramine, in standard laboratory tests,and longer duration of activity of the test compound in the test animal.These characteristics of these compounds will make them useful for theadministration of these compounds as antidepressant drugs in smalleramount and/or for longer durations between administration, e.g., once aday, for a given desired antidepressant response.

This invention also includes a process for treating depression withthese compositions containing these above formula I compounds, orpharmaceutically acceptable salts thereof, and a pharmaceutical carrier,which compositions are useful in dosage unit form for treatingconditions of depression in mammals including humans.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, one aspect of this invention provides newpharmaceutical preparations containing compounds of the formula ##STR3##wherein the wavy line (˜) on the 1-position of the cyclopentyl ringdenotes cis- or trans-configuration relative to the amino group in the2-position of the cyclopentyl ring

p is zero or 1;

Q is oxygen or sulfur;

R is C₁ C₃ -alkyl, C₃ to C₆ -cycloalkyl, vinyl (-CH═CH₂), ethoxy ormethoxymethyl;

R₁, taken separately, is C₁ to C₃ -alkyl;

R₂, taken separately, is C₁ to C₃ -alkyl, and when R₁ is C₁ to C₃-alkyl, R₂ can be

-CH₂ CH₂ N(CH₃)₂,

-ch₂ ch₂ ch₂ n(ch₃)₂,

-ch₂ c₆ h₅ (benzyl),

-CH₂ CH₂ -C₆ H₅, or

C₃ -c₆ (allylic)alkenyl and when R₁ and R₂ are taken together with thenitrogen to which they are bonded they complete an N-pyrrolidinyl or anN-piperidinyl ring;

each of Y and Z is selected from the group consisting of hydrogen, ahalogen having an atomic number of from 9 to 35, trifluoromethyl, C₁ toC₂ -alkyl, azido(-N₃), and C₁ to C₂ -alkyloxy, and when Y istrifluoromethyl or azido Z is hydrogen, when Y is C₁ to C₂ -alkyloxy andZ is hydrogen the C₁ to C₂ -alkyloxy is in the 3-position, when Y and Zare both halogens or C₁ to C₂ -alkyloxy, they are present in 3- and 4-or 3- and 5- positions, and the acid addition salts thereof, preferablythe pharmacologically acceptable acid addition salts thereof. Onoccasion the compounds or their acid addition salts in their crystallinestate are isolated as solvates, i.e., with a discreet quantity ofsolvent, e.g., water, methanol, and the like, associated physically, andthus the solvent is removable without effective alteration of thechemical entity per se and are included with the compounds per seherein.

In the above formula I compounds the term "C₁ to C₃ -alkyl" meansmethyl, ethyl, n-propyl and isopropyl; the term "C₃ to C₆ -cycloalkyl"means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; theterm "C₃ to C₆ -(allylic)alkenyl" includes the non-adjacent double bondgroups, e.g., allyl, 2-butenyl and 2-methyl-2-butenyl, 2-pentenyl,3-methyl-2-pentenyl, and 2-hexenyl groups; and the halogens havingatomic numbers of from 9 to 35 are fluorine, chlorine and bromine.

The preferred compounds of this invention are those of the transconfiguration.

A preferred subgroup of the above compounds are the pharmaceuticalpreparation forms thereof are those wherein R is ethyl; R₁ and R₂ areeach C₁ to C₃ alkyl; and at least one of Y and Z are halogen having anatomic number of from 9 to 35 preferably in the 3- and 4-positions,trifluoromethyl in the 3-position, or methyl in the 3- or 4- position incombination with one of the above halogens at the adjacent 3- or 4-position, and the pharmacologically acceptable salts thereof. Examplesof such compounds include the following:

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide;

3-trifluoromethyl-N-[2-(dimethylamino)cyclopentyl]-propionanilide,

3,4-dichloro-N-[2-(diethylamino)cyclopentyl]propionanilide,

3-chloro-4-methyl-N-[2-(dimethylamino)cyclopentyl]-propionanilide,

4-chloro-4-methyl-N-[2-(dimethylamino)cyclopentyl]-propionanilide,

3-chloro-N-[2-(dimethylamino)cyclopentyl]propionanilide,

4-chloro-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-bromo-N-[2-(dimethylamino)cyclopentyl]propionanilide, and

3-fluoro-N-[2-dimethylamino)cyclopentyl]propionanilide,

especially these compounds in the trans configurations, and thepharmacologically acceptable salts thereof.

Another preferred sub-group of the above compounds are those wherein Ris C₁ to C₃ -alkyl, preferably ethyl, R₁ and R₂ are taken together withthe nitrogen to which they are bonded to complete an N-pyrrolidinyl orN-piperidinyl ring, and at least one of Y and Z is a halogen having anatomic number of from 9 to 35 in the 3- and/or 4- positions. Examples ofsuch compounds include:

3-fluoro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-(N-piperidinyl)cyclopentyl]propionanilide;

3-bromo-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide.

4-chloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide,

3,4-difluoro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, and

3,4-dibromo-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide,

especially these compounds in their trans configuration and thepharmacologically acceptable salts thereof.

Another preferred sub-group of the above compounds are those wherein Ris C₃ to C₆ -cycloalkyl, R₁ and R₂ are C₁ to C₃ -alkyl, and at least oneof Y and Z are halogen having an atomic number of from 9 to 35 in the 3-or 4- position, trifluoromethyl in the 3-position, or methyl in the 3-or 4- position in combination with one of the above halogens in theadjacent 3- or 4-positions, and the pharmacologically acceptable saltsthereof. Examples of such compounds include:

3,4-dichloro-N-[2-dimethylaminocyclopentyl]cyclobutanecarboxanilide,

3,4-dichloro-N-[2-dimethylaminocyclopentyl]cyclohexanecarboxanilide,

3-bromo-4-methyl-N-[2-dimethylaminocyclopentyl]cyclobutanecarboxanilide,

3,4-dichloro-N-[2-dimethylaminocyclopentyl]cyclopropanecarboxanilide,

3-trifluoromethyl-N-[2-diethylaminocyclopentyl]cyclopropanecarboxanilide,

3,4-dibromo-N-[2-diethylaminocyclopentyl]cyclopropanecarboxanilide,

3-chloro-4-methyl-N-[2-dimethylaminocyclopentyl]cyclopropanecarboxanilide,

3-bromo-4-methyl-N-[2-dimethylaminocyclopentyl]cyclohexanecarboxanilide,

3-trifluoromethyl-N-[2-dimethylaminocyclopentyl]cyclohexanecarboxanilide,and

the pharmacologically acceptable salts thereof.

Examples of acid addition salts, including pharmacologically acceptablesalts of the above formula I compounds include those of hydrochloric,methanesulfonic, hydrobromic, sulfuric, acetic, cyclohexanesulfamic,p-toluenesulfonic, succinic, β-naphthalenesulfonic, maleic, fumaric,citric, lactic and oxalic acids.

To use these new compounds in pharmaceutical anti-depressant drugproduct form they are compounded or formulated into usual pharmaceuticalcompositions, e.g., oral dosage forms such as tablets, powders, capsulesand solutions or suspensions in a suitable solvent or suspendingvehicle, and parenteral dosage forms such as dry powder in a sterilesealed container to be mixed with a sterile solvent just prior toadministration, sterile solutions or suspensions in water or othersuitable solvents or suspending agents, to provide a convenient meansfor administering daily doses of from about 1 mg. to about 100 mg.,preferably 10 to 90 mg., of the formula I compound or itspharmacologically acceptable salt, depending upon the potency of theformula I compound, the condition being treated, the weight of thepatient and other factors of concern to the patient's physician.

The formula I compounds where Q is oxygen (═0) and p is zero can beprepared by (a) heating a mixture of a compound of the formula ##STR4##wherein R₁, R₂, Y and Z are as defined above, and an anhydride of theappropriate organic carboxylic acid of the formula R-COOH on a steambath, or at an equivalent temperature, for a time sufficient to form theN-acylated product of the formula I where R is as defined above, Q isoxygen and p is zero, (b) adding an aqueous medium to the step (a)reaction mixture in an amount sufficient to decompose excess anhydridetherein, (c) adding an alkali metal hydroxide or its equivalent to thestep (b) reaction mixture in an amount sufficient to neutralize excessacid present therein and to make the mixture pH basic, (d) extractingthe N-acylated product (I) into a water immiscible organic liquidsolvent, e.g. ether solvents such as diethyl ether, tetrahydrofuran ordioxane, or chloroform, carbon tetrachloride, methylene chloride,ethylene dichloride, or the like, (e) separating the organic liquidphase containing the N-acylated product (I) from the aqueous phase, and(f) recovering the corresponding N-acylated compound (I) from theorganic liquid phase, usually after washing the organic liquid phase oneor more times with aqueous media such as sodium chloride solution,sodium bicarbonate solution or water to extract components soluble inthose aqueous media, separating the aqueous phases, drying the washedorganic phase with drying agents such as magnesium sulfate or sodium orcalcium sulfate, and then evaporating off the organic solvent. Furtherpurification can be done by forming an acid addition salt of theN-acylated amide product (I) and then recrystallizing the amide saltfrom an appropriate solvent or mixture of solvents.

These formula I compounds, immediately above, can also be prepared by(a) adding a solution of the appropriate carboxylic acid halide R-C(O)-Xwhere R is as defined above and X is chloride or bromide to a cooled(-5° to +10° C.) mixture of the diamine (II), and a tertiary amine whichwill form a tertiary amine chloride or bromide salt in the mixture,e.g., a C₁ to C₄ -trialkylamine, e.g., trimethylamine, triethylamine,tributylamine, or pyridine, lutidine, N,N-dimethylaniline or the like,in an organic liquid solvent for the mixture such as an ether solventsuch as diethyl ether, THF, dioxane or the like, while agitating themixture until the corresponding N-acylated compound (I) is formed, (b)adding an aqueous alkali metal bicarbonate solution to the reactionmixture of step (a), (c) separating the aqueous from the organic liquidphases, (d) washing the organic liquid phases with aqueous wash liquidsas described above, (e) drying the organic phase, and (f) recovering theN-acylated compound (I) from the resulting organic liquid mixture. TheN-acylated amide compound (I) can be further purified by formation of anacid addition salt thereof, e.g., the hydrochloric acid, or maleic acidaddition salt thereof, and re-crystallization of the amide salt from anappropriate solvent or solvent mixture.

The formula I compounds which do not contain a reactive aliphaticcarbon-to-carbon double bond in the molecule, that is, those wherein Qis oxygen (═O) and p is zero, can be converted to their N-oxides byreaction of such formula I aminoamide or its salt with a percarboxylicacid by known procedures to obtain the corresponding formula I compoundwhere p is 1.

The corresponding N-thioacyl amino anilide compounds can be prepared byheating to reflux the corresponding N-acyl(C═O) amino anilide (formula Icompound) with a thiolating agent such as phosphorus pentasulfide ordiethyl-dithiophosphate (P(S)SH(OC.sub. 2 H₅)₂) in an appropriatesolvent such as pyridine for a time sufficient to effect replacement ofthe acyl oxygen atom with sulfur, and then recovering and purifying theN-thioacyl aminoanilide compound by known procedures. If the N-oxides ofthe Q is S compounds are to be made, the N-oxide is prepared first andthe resulting N-oxide is thiolated as described above to form theformula I compound where Q is ═S and p is 1.

Further exemplification of these process procedures appear in thedetailed examples.

The trans-diamine starting materials (II) of the formula ##STR5##wherein R₁, R₂, Y and Z are as defined above can be prepared by reacting1,2-cyclopentene oxide (IIIa) ##STR6## with the selected HNR₁ R₂ aminein water to form the trans-2-aminocyclopentanol of the formula IIIb##STR7## which amino-alcohol (IIIb) is treated with sodium hydride andthen with methanesulfonyl chloride to form unrecovered mesylate of theformula IV ##STR8## wherein Ms denotes CH₃ SO₂ -group and that reactionmixture is treated with the selected substituted aniline of formula V##STR9## to form the diamine (II). Examples of this procedure are givenhereinbelow in the detailed descriptions.

Examples of the carboxylic acid anhydrides which can be used to preparethe compounds of this invention include acetic anhydride, pripionicanhydride, isobutanoic anhydride, n-butanoic anhydride,cyclopropanecarboxylic acid anhydride, acrylic acid anhydride, and thelike. The preferred anhydride is propionic acid anhydride. Thecarboxylic acid haides are exemplified by acetyl chloride or bromide,propionyl chloride or bromide, acryloyl chloride or bromide,cyclohexanecarbonyl chloride or bromide, n- and isobutanoylchloride orbromide, cyclopropanecarbonyl chloride or bromide, ethyl formate,methoxyacetyl chloride or bromide and the like. We have found that, ingeneral, the most potent antidepressant compounds are made from thosecompounds having an N-propionyl moiety, so that in the formula Icompounds R is preferably ethyl.

When it is desired that the formula I have an allyl group in the R₂position an alternate method can also be used: the amino-amide isprepared as described above using an alkyl benzylamine to form theamino-alcohol (IIIb), and that amino-alcohol is carried through theintermediate (IV), and (V) reactions to form the diamine. The resultingdiamine is then hydrogenated catalytically, preferably in the presenceof palladium on carbon catalyst, to remove the benzyl group in the R₂position and form the transdiamine of the formula VI. ##STR10## Thetrans-diamine (VI) is then reacted with the allylic alkenyl chloride orbromide to form the diamine of the formula VII ##STR11## which diamine(VII) is used as an intermediate in a reaction with the selectedcarboxylic acid anhydride or acid chloride or bromide as describedabove, to form the N-acylated product of the formula ##STR12## in whichformulas Ia, IIIb, IV, V, VI, VII and VIII, R, R₁, Y and Z are asdefined above.

Preparation of cis amino amide compound of invention:

The method of J. W. Lewis et al., J. Pharm. Sci., 63, 1951 (1974) using1-dialkylaminocyclopentene (enamine) and nitrosoaryl as startingmaterials can be used to obtain cis-1,2-diaminocyclopentane which issubsequently reacted with carboxylic acid anhydride or carboxylic acidhalide as described above to give the product amino-amide.

A preferred method, which is that used for this invention involvesreaction of cyclopentene oxide with an aniline in the presence of strongacid to give the compound of formula ##STR13## which is subsequentlyreacted with carboxylic acid anhydride followed by reaction with base toisolate the compound of formula ##STR14## oxidation of the alcohol leadsto the compound of formula ##STR15## which when reacted with primary orsecondary amine and a reducing agent such as sodium cyanoborohydride,and the like, gives a compound of the formula ##STR16## wherein R₂ isnot C₃ -C₆ (allylic)alkenyl. Cis compounds wherein R₂ is C₃ to C₆-(allylic)alkenyl can be prepared analogously to the corresponding transcompounds; in that case a primary amine is used with the reducing agentfollowed by the allylic alkenyl chloride or bromide.

The thio analogs of such cis amino-amides can be prepared as describedearlier in this specification.

Examples of additional useful compounds of formula I of this inventioninclude the following compound, preferably in their trans-configuration

N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-methyl-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-methoxy-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-{2-[N-methyl-N-(2-dimethylaminoethyl)amino]cyclopentyl}propionanilide,

3,4-dichloro-N-{2-[N-methyl-N-(3-dimethylaminopropyl)amino]cyclopentyl}propionanilide,

N-[2-(dimethylamino)cyclopentyl]acetanilide,

N-[2-(dimethylamino)cyclopentyl] butyranilide,

3-trifluoromethyl-N-[2-(N-methyl-N-benzylamino)cyclopentyl]propionanilide,

3,4-dibromo-N-{2-[N-ethyl-N-(2-phenylethyl)amino]cyclopentyl}propionanilide

3-chloro-4-methyl-N-[2-(N-methyl-N-allylamino)cyclopentyl]propionanilide,

4-bromo-3-methyl-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide,

3,4-difluoro-N-{2-[N-methyl-N-(2-dimethylaminoethyl)amino]cyclopentyl}propionanilide,

3-chloro-4-fluoro-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dibromo-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dimethyl-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]butyranilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]-N-cyclopropanecarboxanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]thio-propionanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]-N-acrylanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]isobutyranilide,

3-bromo-N-[2-(N-methyl-N-benzylamino)cyclopentyl]butyranilide,

3-chloro-4-fluoro-N-[2-(N-pyrrolidinyl)cyclopentyl]cyclopropanecarboxanilide,

3,5-dibromo-N-[2-(N-methyl-N-2-phenylethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-dimethylaminocyclopentyl]methoxyacetanilide,

3,4-dichloro-N-[2-dimethylaminocyclopentyl]carbethoxyanilide,

3-methyl-4-chloro-N-[2-diethylaminocyclopentyl]propionanilide,

3-trifluoromethyl-N-{2-(N-methyl-N-2-butenyl]aminocyclopentyl}cyclohexanecarboxanilide,

3-ethoxy-4-bromo-N-[2-dimethylaminocyclopentyl]propionanilide,

4-azido-N-[2-(dimethylamino)cyclopentyl]propionanilide, and the like,the 2-N-oxides of the above compounds which do not contain aliphaticunsaturation, and their acid addition salts.

If desired the formula I compounds of this invention can be resolvedinto their respective d- and l-optical isomers by methods known in theart. In this case the optical resolution can be done by at least twodifferent routes. The resolving agents by either route are any of theknown resolving agents such as optically active camphorsulfonic acid,bis-p-toluoyltartaric acid, tartaric acid, and diacetyl tartaric acidwhich are commercially available and which are commonly used forresolution of amines (bases) as for example in Organic Syntheses, Coll.Vol. V., p. 932 (1973), resolution of R-(+) and S-(-)-α-phenylethylamine with (+)-tartaric acid.

By the first method for resolving the compounds of this invention, forexample, one of the amino amide compounds can be converted into itsoptically active diastereomeric salts by reaction with an opticallyactive acid--examples of which are mentioned above--in a manner standardin the isomer resolution art. These diastereomeric salts can then beseparated by conventional means such as differential crystallization.Diastereomeric salts have different crystallization properties, whichare taken advantage of this separation. On neutralization eachdiastereomeric salt with aqueous base the corresponding optically activeof the free amino-amide can be obtained, each of which can subsequentlyand separately be converted as previously described in the examples tothe desired acid addition salt.

By the second method, which in the case of some of these compounds ispreferred, the formula I compound can be made into their respective d-and l-isomers, by first resolving cis- or trans-1,2-cycloaliphaticunsymmetrically substituted diamine into its respective d- and l-isomersby treatment with the resolving agent, crystallization, separation, andregeneration of the respective trans-d-diamine, trans-l-diamine, or thecis-d-diamine and cis-l-diamine, and then reacting the respectiveresolved diamine starting matrial with the desired carboxylic acidanhydride or halide to form the respective cis- or trans-d- orl-compound of formula I, which can then be converted to any desiredpharmaceutically acceptable acid addition salt by procedures exemplifiedabove.

If the acid addition salt used to extract the formula I compound fromits reaction mixture is not itself pharmacologically acceptable, thefree amino-amide base (I) can be prepared from the acid salt, andthereafter converted to a pharmacologically acceptable salt, by knownprocedures.

In the use of these compounds of formula I as antidepressant drugs theselected compound of formula I which is to be the antidepressant activeingredient is mixed with suitable pharmaceutical diluents to obtainpharmaceutical compositions suited for oral, parenteral and rectal usein dosage unit form, e.g., tablets, powder packets, cashets, dragees,capsules, solutions, suspensions, sterile injectable forms,suppositories, bougies, and the like. Suitable diluents or carriers suchas carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used ascarriers or for coating purposes. Water and oils, e.g., coconut oil,sesame oil, safflower oil, cottonseed oil, peanut oil may be used forpreparing solutions or suspensions of the active drug. Sweetening,coloring and flavoring agents may be added. The specifications for thedosage unit forms of these formula I compounds will vary somewhat fromcompound to compound and dependent upon the physical characteristics ofthe formula I compound or its pharmacologically acceptable salt, theparticular patient's weight and age, and the particular effect sought tobe achieved. The pharmaceutical dosage unit forms of these compounds areprepared in accordance with the preceding general description to providefrom about 1 to about 100 mg. of the formula I compound or itspharmacologically acceptable salt per dosage unit form. The amount ofthe formula I compound prescribed in pharmaceutical dosage unit form isthat amount sufficient to obtain in the patient a relief from thecondition of depression effect at a non-toxic dosage level.

The following detailed procedures and examples further describe andillustrate how to make and use the starting amines and the compounds ofthis invention. All temperatures are in degrees Centigrade unlessotherwise indicated. For brevity, the term THF means tetrahydrofuran,NMR means nuclear magnetic resonance spectrum, IR means infraredspectrum, UV means ultraviolet spectrum, ether means diethyl ether, NaOHmeans sodium hydroxide, MgSO₄ means anhydrous magnesium sulfate, andMeOH means methanol.

I. General procedure for the preparation of trans-2-aminocycloalkanols

The procedure is exemplified by the preparation oftrans-2-dimethylaminocyclopentanol. Analogs are listed in Table I. Allcompounds listed have NMR, IR, UV and mass spectra consistent with therespective structures. ##STR17## A mixture of cyclopentene oxide (188g., 2.24 moles) and aqueous dimethylamine (40%, 750 ml., 6.67 moles) isstirred overnight (temperature rises to 45° after 1 hr. then subsides).The solution (750 ml.) and extracted several times with ether. Theextract is dried (anhydrous MgSO₄) and concentrated by distillation. Theresidual oil is vacuum distilled to give 276 g. (90%) oftrans-2-dimethylaminocyclopentanol, b.p. 98°-100°14 mm; uv (EtOH): endabsorption; IR: OH 3370, 3200, N-alkyl 2780, C-O 1045 cm⁻¹ ; massspectrum: M⁺ 129; nmr (CDCl₃): δvar (br, 1H exchanges with D₂ O, OH),3.9-4.3 (m, 1H, CH), 2.3-2.6 (m, 1H, CH), 2.28 (s, 6H, N(CH₃)₂), 1.2-2.0(m, 6H, ring hydrogens). The analysis (fumaric acid salt), is given inTable I.

Table I which follows summarizes the physical analytical data for some2-aminocyclopentanols which were prepared. The particular 2-amino moietyfor each such compound is indicated by the indicated group in the -NR₁R₂ column.

The process utilized to prepare the trans cyclopentane diamineintermediates of this invention is unique and believed to be new or atleast an unobvious improvement in that attempts to prepare cyclopentanediamines based on analogy to the cyclohexane diamine chemistry work veryinefficiently. More specifically, and for example, the reaction ofthionyl chloride with cyclohexane 2-amino-alcohols proceeds smoothly togive the cyclohexane 2-amino halides which proceeds further on reactionwith the selected amine to give the cyclohexane 1,2-diamine. In the caseof cyclopentane compounds, reaction of thionyl chloride with theamino-alcohol followed by reaction with the selected amine results inonly a small yield of the desired cyclopentane diamine; the majorproduct of such reaction is IX, e.g., ##STR18## whereas, use ofmethanesulfonyl chloride, as indicated in the above description formsthe good leaving group (mesylate) and gives respectable yields of thedesired 1,2-cyclopentanediamine precursor to the compounds of thisinvention. This process is not self-evident on the basis ofcorresponding cyclohexane ring chemistry.

                                      TABLE I                                     __________________________________________________________________________    trans-2-aminocyclopentanols                                                    ##STR19##                                                                    Starting                                                                      Materials                                   Analysis                          Number                                                                             NR.sub.1 R.sub.2                                                                          b.p.(° C.)                                                                      m.p.(° C.)                                                                   Formula      Calcd.                                                                              Found                      __________________________________________________________________________    A    N(CH.sub.3)CH.sub.2 CH.sub.3                                                              102°-4° /13 mm                                                           94°-96° .sup.5,a                                                      C.sub.8 H.sub.17 NO . C.sub.4 H.sub.4                                         O.sub.4     C,                                                                              55.58;                                                                            C,                                                                              55.92;                                                                H,                                                                              8.16;                                                                             H,                                                                              8.17;                                                                 N,                                                                              5.40                                                                              N,                                                                              5.54                      B    N(CH.sub.2 CH.sub.3).sub.2                                                                107°-8° /14 mm                                                           134°-5° .sup.5,a                                                      C.sub.9 H.sub.13 NO . C.sub.4 H.sub.4                                         O.sub.4     C,                                                                              57.12;                                                                            C,                                                                              57.20;                                                                H,                                                                              8.48;                                                                             H,                                                                              8.54;                                                                 N,                                                                              5.13                                                                              N,                                                                              5.10                            ##STR20##  130°-1° /14 mm                                                           115°-6° .sup.5,a                                                      C.sub.9 H.sub.17 NO . C.sub.7 H.sub.7                                         SO.sub.3 H  C, H, N, S,                                                                     58.67; 7.70; 4.29; 9.79                                                           C, H, N, S,                                                                     58.99; 8.05; 4.19;                                                            10.07                     D    N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                       134°-40° /0.3 mm                                                         95°-7° .sup.5,a                                                       C.sub.13 H.sub.19 NO . C.sub.4 H.sub.4                                        O.sub.4     C,                                                                              63.53;                                                                            C,                                                                              63.45;                                                                H,                                                                              7.21;                                                                             H,                                                                              7.31;                                                                 N,                                                                              4.36                                                                              N,                                                                              4.32                      E    N(CH.sub.3)CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                              134°-40° /0.3 mm                                                         139°-41° .sup.5,a                                                     C.sub.14 H.sub.21 NO . 1/2 C.sub.4                                            H.sub.4 O.sub.4                                                                           C,                                                                              69.28;                                                                            C,                                                                              69.25;                                                                H,                                                                              8.36;                                                                             H,                                                                              7.31;                                                                 N,                                                                              5.05                                                                              N,                                                                              5.12                      F    N(CH.sub.3)CH.sub.2 CHCH.sub.2                                                            108°-9° /13 mm                                                            --   C.sub.9 H.sub.17 NO                                                                         --    --                        G    N(CH.sub.3).sub.2                                                                         98° /12 mm                                                                      149°-51° .sup.5,a                                                     C.sub.7 H.sub.15 NO . 1/2 C.sub.4 H.sub.4                                     O.sub.4     C,                                                                              57.73;                                                                            C,                                                                              57.35;                                                                H,                                                                              9.15;                                                                             H,                                                                              9.03;                                                                 N,                                                                              7.48                                                                              N,                                                                              7.11                      H    N(CH.sub.3)CH.sub.2 CH.sub.2 N                                                            98°/0.2 mm                                                                      135°-6° .sup.4,a                                                      C.sub.10 H.sub.22 N.sub.2 O . C.sub.4                                         H.sub.4 O.sub.4                                                                           C,                                                                              51.55;                                                                            C,                                                                              51.63;                         (CH.sub.3).sub.2                       H,                                                                              7.23                                                                              H,                                                                              7.39;                                                                 N,                                                                              6.70                                                                              N,                                                                              6.71                      J    N(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.2 N                                                   115°-8° /0.2 mm                                                          137°-8° .sup.4,a                                                      C.sub.11 H.sub.24 N.sub.2 O . C.sub.4                                         H.sub.4 O.sub.4                                                                           C,                                                                              52.76;                                                                            C,                                                                              53.00;                         (CH.sub.3).sub.2                       H,                                                                              7.46;                                                                             H,                                                                              7.82;                                                                 N,                                                                              6.48                                                                              N,                                                                              6.43                      __________________________________________________________________________     Recrystallization solvent                                                     .sup.a methanol-ether                                                         .sup.b ethanol-ether                                                          .sup.c petroleum ether                                                        .sup.d ether                                                                  .sup.e petroleum ether-ether                                                  .sup.f benzene                                                                Derivative                                                                    .sup.1 free base                                                              .sup.2 hydrochloride                                                          .sup.3 hydrochromide                                                          .sup.4 maleate                                                                .sup.5 fumarate                                                               .sup.6 oxalate                                                                .sup.7 2-naphthalenesulfonate                                                 .sup.8 p-tolueneslfonate                                                      .sup.9 methanesulfonate                                                  

II. General procedure for the preparation oftrans-1,2-diaminocycloalkanes

The procedure is exemplified by the preparation oftrans-N,N-dimethyl-N'-(3,4-dichlorophenyl)-1,2-cyclopentanediamine.Analogs are listed in Table II. All compounds listed have NMR, IR, UV,and mass spectra consistent with the respective structures. ##STR21## Asolution of trans-2-(dimethylamino)cyclopentanol (32.3 g., 0.25 mole) inTHF (50 ml.) is added in one portion to a stirred suspension of sodiumhydride (10.5 g., 57% dispersion in mineral oil, 0.25 mole) in THF (50ml.), and the mixture refluxed for 1 hr. The mixture is cooled in icewhile methanesulfonyl chloride (28.6 g., 0.25 mole) is added dropwiseover 30 min. 3,4-Dichloroaniline (81.0 g., 0.50 mole) is added in oneportion when the methanesulfonyl chloride addition is complete. Thesolvent is removed by distillation, and the residue heated on a steambath overnight. Sodium hydroxide (200 ml., 20%) is added and heatingcontinued for 1 hr. The mixture is extracted with ether. The organicphase is washed with water and extracted with 10% hydrochloric acid. Theaqueous phase is washed with ether, made basic with 40% sodiumhydroxide, and extracted with ether. The ether layer is washed withsaturated sodium chloride solution, dried (anhydrous MgSO₄) andevaporated. The residual oil is distilled at reduced pressure to give,after a forerun consisting mainly of 3,4-dichloroaniline (65.7 g.), 36.2g. (53%), 3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]aniline, bp160°-70°/0.3 mm. The distillate is further purified by formation of themaleic acid salt and recrystallization from methanol-ether; mp 128°-29°;uv (EtOH): λ_(max) (ε) 210 (45,450), 257 (19,400), 310 (2300) nm; IR:NH3380, NH/acid OH 2600, 2520, 2400, CO₂ /C═C/NH def 1600, 1580, 1480,C--H/C--N/CO₂ ⁻ 1430, 1350, 1330, other 985, 870, 865 cm⁻¹ ; massspectrum: M⁺ 272, 274 (free base); nmr (D₂ O): δ 7.1 (m, 1H, aromatic),6.7 (m, 1H, aromatic), 6.5 (m, 1H, aromatic), 6.1 (s, 2H, vinyl, maleicacid) 3.8 (m, 1H, CH), 3.35 (m, 1H, CH), 2.75 (s, 6H, N(CH₃)₂), 1.2-2.3(m, 6H, ring hydrogens).

Anal. Calcd. for C₁₃ H₁₈ Cl₂ N₂ ·C₄ H₄ O₄ : Calcd.: C, 52.45; H, 5.70;Cl, 18.22; N, 7.20. Found: C, 52.48; H, 5.80; Cl, 18.41; N, 7.07.

                                      TABLE II                                    __________________________________________________________________________    trans-1,2-diaminocyclopentanes                                                 ##STR22##                                                                                                                     Analysis                     No.                                                                              Y/Z   N R.sub.1 R.sub.2                                                                      b.p. (° C.)                                                                      m.p.(° C.)                                                                     Formula        Calcd. Found               __________________________________________________________________________    A  H     N(CH.sub.3).sub.2                                                                      97°-103° /0.05 mm                                                         31°-2° .sup.1                                                           C.sub.13 H.sub.20 N.sub.2                                                                  C, 76.42;                                                                            C, 76.42;                                                              H, 9.87;                                                                             H, 9.89;                                                               N, 13.71                                                                             N, 13.61              B  2-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                      120°-5° /0.1 mm                                                           180°-1° .sup.2,a                                                        C.sub.14 H.sub.22 N.sub.2 .                                                                C,Cl                                                                             57.73;                                                                            C, 58.51;                                                              H, 8.31;                                                                             H, 8.48;                                                               Cl,                                                                              24.35;                                                                            Cl,                                                                              23.19;                                                              N, 9.62                                                                              N, 10.11              C  3-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                      120°-5° /0.1 mm                                                           188°  .sup.2,a                                                                 C.sub.14 H.sub.22 N.sub.2 .                                                                C,Cl                                                                             57.73;                                                                            C, 57.96;                                                              H, 8.31;                                                                             H, 8.26;                                                               Cl,                                                                              24.35;                                                                            Cl,                                                                              24.14;                                                              N, 9.62                                                                              N, 9.88               D  4-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                      125°-35° /0.1 mm                                                          198°-                                                                          C.sub.14 H.sub.22 N.sub.2 .                                                                C,Cl                                                                             57.73;                                                                            C, 58.04;                                         200° .sup.2,a H, 8.31;                                                                             H, 8.40;                                                               Cl,                                                                              24.35;                                                                            Cl,                                                                              24.06;                                                              N, 9.62                                                                              N, 9.80               E  2-Cl  N(CH.sub.3).sub.2                                                                      125°-35° /0.1 mm                                                          93°-5° .sup.4,a                                                         C.sub.13 H.sub.19 ClN.sub.2 . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 57.74;                                                                            C, 57.41;                                                              H, 6.53;                                                                             H, 6.51;                                                               Cl,                                                                              9.99;                                                                             Cl,                                                                              9.84;                                                               N, 7.90                                                                              N, 7.56               F  3-Cl  N(CH.sub.3).sub.2                                                                      140°-4° /0.2 mm                                                           125°-7° .sup.4,a                                                        C.sub.13 H.sub.19 ClN.sub.2 . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 57.74;                                                                            C, 57.40;                                                              H, 6.53;                                                                             H, 6.60;                                                               Cl,                                                                              9.11;                                                                             Cl,                                                                              9.80;                                                               N, 7.90                                                                              N, 8.00               G  4-Cl  N(CH.sub.3).sub.2                                                                      140°-5° /0.2 mm                                                           41°-2° .sup.1,c                                                         C.sub.13 H.sub.19 ClN.sub.2                                                                C, 65.39;                                                                            C, 65.63;                                                              H, 8.02;                                                                             H, 7.99;                                                               Cl,                                                                              14.85;                                                                            Cl,                                                                              14.81;                                                              N, 11.74                                                                             N, 11.88              H  3-OCH.sub.3                                                                         N(CH.sub.3).sub.2                                                                      125°-32° /0.01 mm                                                         77°-8° .sup.4,a                                                         C.sub.14 H.sub.22 N.sub.2 O . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 61.69;                                                                            C, 61.69;                                                              H, 7.48;                                                                             H, 7.40;                                                               N, 8.00                                                                              N, 7.93               J  4-OCH.sub.3                                                                         N(CH.sub.3).sub.2                                                                      140°-50° /0.3 mm                                                          85°-7° .sup.4,a                                                         C.sub.14 H.sub.22 N.sub.2 O . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 61.69;                                                                            C, 61.71;                                                              H, 7.48;                                                                             H, 7.47;                                                               N, 8.00                                                                              N, 7.98               K  3-F   N(CH.sub.3).sub.2                                                                      115°-18° /0.3 mm                                                          137°-8° .sup.4,a                                                        C.sub.13 H.sub.19 N.sub.2 F . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 60.34;                                                                            C, 60.38;                                                              H, 6.85;                                                                             H, 7.00;                                                               F, 5.62;                                                                             F, 5.37;                                                               N, 8.28                                                                              N, 8.14               L  4-F   N(CH.sub.3).sub.2                                                                      125°-8° /0.1 mm                                                           156°-7° .sup.4,a                                                        C.sub.13 H.sub.19 FN.sub.2 . C.sub.4                                          H.sub.4 O.sub.4                                                                            C, 58.77;                                                                            C, 58.80;                                                 1/2 H.sub.2 O                                                                              H, 6.96;                                                                             H, 6.70;                                                               F, 5.47;                                                                             F, 5.37;                                                               N, 8.07                                                                              N, 7.85               M  3-Br  N(CH.sub.3).sub.2                                                                      140°-4° /0.3 mm                                                           114°-15° .sup.4,a                                                       C.sub.13 H.sub.19 BrN.sub.2 . C.sub.4                                         H.sub.4 O.sub.4                                                                            C, 51.13;                                                                            C, 51.54;                                                              H, 5.81;                                                                             H, 5.97;                                                               N, 7.02;                                                                             N, 19.74;                                                              Br,                                                                              20.02                                                                             Br,                                                                              7.02               N  4-Br  N(CH.sub.3).sub.2                                                                      130°-7° /0.1 mm                                                           44°-5° .sup.1,c                                                         C.sub.13 H.sub.19 BrN.sub.2                                                                C, 55.13;                                                                            C, 55.08;                                                              H, 6.76;                                                                             H, 6.84;                                                               Br,                                                                              28.22;                                                                            Br,                                                                              28.43;                                                              N, 9.89                                                                              N, 9.54               P  4-CH.sub.2 CH.sub.3                                                                 N(CH.sub.3).sub.2                                                                      125°-30° /0.2 mm                                                          125°-7° .sup.7,a                                                        C.sub.15 H.sub.24 N.sub.2 . C.sub.10                                          H.sub.8 SO.sub.3                                                                           C, 65.47;                                                                            C, 65.87;                                                 . 1/2 H.sub.2 O                                                                            H, 7.47;                                                                             H, 7.52;                                                               N, 6.11;                                                                             N, 6.06;                                                               S, 6.99                                                                              S, 7.14               R  3,4-diCl                                                                            N(CH.sub.3).sub.2                                                                      155°-60° /0.3 mm                                                          128°-9° .sup.4,a                                                        C.sub.13 H.sub.18 Cl.sub.2 N.sub.2 .                                          C.sub.4 H.sub.4 O.sub.4                                                                    C, 52.45;                                                                            C, 52.48;                                                              H, 5.70;                                                                             H, 5.80;                                                               Cl,                                                                              18.22;                                                                            Cl,                                                                              18.41;                                                              N, 7.20                                                                              N, 7.07               S  3,5-diCl                                                                            N(CH.sub.3).sub.2                                                                       --*      147°-9° .sup.2,a                                                        C.sub.13 H.sub.18 Cl.sub.2 N.sub.2 .                                          2HCl         C, 45.11;                                                                            C, 45.13;                                                              H, 5.82;                                                                             H, 5.72;                                                               Cl,                                                                              40.97;                                                                            Cl,                                                                              40.46;                                                              N, 8.09                                                                              N, 7.97               T  3,4-diCH.sub.3                                                                      N(CH.sub.3).sub.2                                                                      170°-80° /0.2 mm                                                          158°-9° .sup.5,a                                                        C.sub.15 H.sub.24 N.sub.2 O.sub.2 .                                           C.sub.4 H.sub.4 O.sub.4                                                                    C, 59.93;                                                                            C, 60.21;                                                              H, 7.42;                                                                             H, 7.56;                                                               N, 7.37                                                                              N, 7.18               U  3-CF.sub.3                                                                          N(CH.sub.3).sub.2                                                                      115°-17° /0.2 mm                                                          107°-8° .sup.4,a                                                        C.sub.14 H.sub.19 F.sub.3 N.sub.2 .                                           C.sub.4 H.sub.4 O.sub.4                                                                    C, 55.66;                                                                            C, 55.76;                                                              H, 5.97;                                                                             H, 6.06;                                                               F, 14.68;                                                                            F, 14.50;                                                              N, 7.21                                                                              N, 7.01               V  4-CF.sub. 3                                                                         N(CH.sub.3).sub.2                                                                      116°-20° /0.2 mm                                                          95°-6° .sup.2,a                                                         C.sub.14 H.sub.19 F.sub.3 N.sub.2                                                          C, 58.88;                                                                            C, 58.47;                                                 . C.sub.10 H.sub.6 SO.sub.3 . 1/2                                             H.sub.2 O    H, 5.76;                                                                             H, 6.07;                                                               F, 11.64;                                                                            F, 11.47;                                                              N, 5.72;                                                                             N, 5.35;                                                               S, 6.55                                                                              S, 6.56               W  3-Cl  N(CH.sub.3).sub.2                                                                      140°-5° /0.3 mm                                                           207°-8° .sup.2,a                                                        C.sub.14 H.sub.21 ClN.sub.2 .                                                              C,Cl                                                                             51.62;                                                                            C, 51.62;                4-CH.sub.3                                    H, 7.12;                                                                             H, 7.12;                                                               Cl,                                                                              32.65;                                                                            Cl,                                                                              32.26;                                                              N, 8.59                                                                              N, 8.60               AA 4-Cl  N(CH.sub.3).sub.2                                                                      140°-50° /0.3 mm                                                          201°-2° .sup.2,a                                                        C.sub.14 H.sub.21 ClN.sub.2 .                                                              C,Cl                                                                             51.62;                                                                            C, 51.55;                3-CH.sub.3                                    H, 7.12;                                                                             H, 7.07;                                                               Cl,                                                                              32.65;                                                                            Cl,                                                                              32.51;                                                              N, 8.59                                                                              N, 8.53               BB H     N(CH.sub.3)CH.sub.2                                                                    116°-30° /0.2 mm                                                          195°-200° .sup.3,a                                                      C.sub.14 H.sub.22 N.sub.2 .                                                                C,Br                                                                             44.23;                                                                            C, 44.14;                      CH.sub.3                                H, 6.36;                                                                             H, 6.46;                                                               Br,                                                                              42.02;                                                                            Br,                                                                              42.29;                                                              N, 7.37                                                                              N, 7.04               CC 3,4-diCl                                                                            N(CH.sub.2 CH.sub.3).sub.2                                                             155°-60° /0.3 mm                                                          186°-8° .sup.2,a                                                        C.sub.15 H.sub.22 ClN.sub.2 .                                                              C,Cl                                                                             48.14;                                                                            C, 48.40;                                                              H, 6.46;                                                                             H, 6.37;                                                               Cl,                                                                              37.90;                                                                            Cl,                                                                              37.49;                                                              N, 7.49                                                                              N, 7.70               DD 3,4-diCl                                                                             ##STR23##                                                                             160°-70° /0.3 mm                                                          185°-7° .sup.2,a                                                        C.sub.15 H.sub.20 Cl.sub.2 N.sub.2 .                                          2HCl         C, H, Cl, N,                                                                     48.40;  5.96; 38.11;                                                          .53 C, H, Cl,                                                                        48.53;  6.00;                                                                 38.35;  7.44       EE H     N(CH.sub.3)                                                                            160°-75° /0.25 mm                                                         109°-10° .sup.2,a                                                       C.sub.19 H.sub.24 H.sub.2 . C.sub.4                                           H.sub.4 O.sub.4                                                                            C, 69.67;                                                                            C, 69.60;                      CH.sub.2 C.sub.6 H.sub.5                H, 7.12;                                                                             H, 7.43;                                                               N, 7.08                                                                              N, 6.90               FF 3,4-diCl                                                                            N(CH.sub.3)                                                                            170°-80° /0.3 mm                                                          170°-2° .sup.2,a                                                        C.sub.15 H.sub.20 N.sub.2 Cl.sub.2 .                                          2HCl         C, 48.40;                                                                            C, 48.36;                      CH.sub.2 CHCH.sub.2                     H, 5.96;                                                                             H, 6.15;                                                               N, 7.53;                                                                             N, 7.54;                                                               Cl,                                                                              38.11                                                                             Cl,                                                                              38.36              GG 3,4-diCl                                                                            N(CH.sub.3)CH.sub.2                                                                     --*      161°-2°                                                                 C.sub.10 H.sub.25 Cl.sub.2 N.sub.3                                                         C, 51.25;                                                                            C, 51.33;                      CH.sub.2 N(CH.sub.3).sub.2 . 2C.sub.4 H.sub.4 O.sub.4                                                                 H, 5.91;                                                                             H, 6.13;                                                               Cl,                                                                              12.61;                                                                            Cl,                                                                              12.46;                                                              N, 7.47                                                                              N, 7.27               HH 3,4-diCl                                                                            N(CH.sub.3)                                                                             --*      155°-7° .sup.4,a                                                        C.sub.17 H.sub.27 Cl.sub.2 N.sub.3                                                         C, 52.09;                                                                            C, 51.91;                      CH.sub.2 CH.sub.2 CH.sub.2 . 2C.sub.4 H.sub.4 O.sub.4                                                                 H, 6.12;                                                                             H, 6.26;                       N(CH.sub.3).sub.2                       Cl,                                                                              12.30;                                                                            Cl,                                                                              12.53;                                                              N, 7.28                                                                              N, 7.23               __________________________________________________________________________     Derivative                                                                    .sup.1 free base                                                              .sup.2 hydrochloride                                                          .sup.3 hydrobromide                                                           .sup.4 maleate                                                                .sup.5 fumarate                                                               .sup.6 oxalate                                                                .sup.7 2-naphthalene sulfonate                                                .sup.8 p-toluenesulfonate                                                     .sup.9 methanesulfonate                                                       Recrystallization Solvent                                                     .sup.a methanol-ether                                                         .sup.b ethanol-ether                                                          .sup.c petroleum ether                                                        .sup.d ether                                                                  .sup.e petroleum ether-ether                                                  .sup.f benzene                                                                *isolated by silica gel chromatography                                   

EXAMPLE 1 III. General procedure A for the preparation oftrans-N-(2-aminocyclopentyl)anilides, using alkanoic acid anhydride

The procedure is exemplified by the preparation oftrans-N-[2-(dimethylamino)cyclopentyl]-3',4'-dichloropropionanilide.Analogs are listed in Tables III and IV. All compounds listed have NMR,IR, UV, and mass spectra consistent with the respective structuresassigned ##STR24## A solution of3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]aniline (2.73 g., 10.0mmole) in propionic anhydride (10 ml.) is heated on a steam bathovernight. Water (100 ml.) is added and heating continued for 1 hr. todecompose excess anhydride. The solution is made basic with sodiumhydroxide (25 ml., 20% aqueous) and extracted with ether. The extract iswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yellow oil. The crude amide product,3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide is purifiedby formation of the maleic acid salt and recrystallization frommethanol-ether; 3.3 g. (74%) mp 154°-5°; uv (EtOH): λ_(max) (ε) endabsorption, 203 (61,350), 264 (sh, 828), 272 (744), 281 (592) nm;IR:NH/acid OH 2720, 2530, 2490, C═O/CO₂ ⁻ /C═C 1665, 1620, 1560C═O/C--N/other 1355, 1265 1030, 865 cm⁻¹ ; mass spectrum; M⁺ 328, 330,332, (free base); nmr (D₂ O): δ 7.6 (m, 1H, aromatic), 7.5 (m, 1H,aromatic), 7.3 (m, 1H, aromatic), 6.3 (s, 2H, maleic acid), 5.1 (m, 1H,CH), 3.8 (m, 1H, CH), 2.95 (s, 6H, N⁺ (CH₃)₂), 2.0 (q, 2H, CH₃ CH₂ CO),1.1-1.9 (m, 6H, ring hydrogens), 0.9 (t, 3H, CH₃ CH₂ CO).

Anal. Calcd. for C₁₆ H₂₂ Cl₂ N₂ O·C₁ H₄ O₄ : Calcd.: C, 53.94; H, 5.89;Cl, 15.95; N, 6.29. Found: C, 53.91; H, 5.82, Cl, 15.82; N, 6.33.

EXAMPLE 2 IV. General procedure B for the preparation oftrans-N-(2-aminocyclopentyl)anilides, using alkanoyl halides

The procedure is exemplified by the preparation oftrans-N-[(2-dimethylamino)cyclopentyl]-4'-(α, α, α-trifluoromethyl)-propionanilide. Analogs are listed in Tables III andIV. All compounds listed have NMR, IR, UV and mass spectra consistentwith the respective structures assigned. ##STR25## A solution ofpropionyl chloride (2.11 g., 22.0 mmole) in ether (50 ml.) is addeddropwise, with ice-cooling, in 30 min. to a solution of the4-trifluoromethyl-N-[2-(dimethylamino)cyclopentyl]aniline (3.10 g., 11.0mmole) and triethylamine (2.30 g., 22.0 mmole) in ether (100 ml.). Afterstirring at room temperature overnight, saturated sodium bicarbonatesolution (100 ml.) is added. The organic layer is washed with water andsaturated sodium chloride solution, dried (MgSO₄) and evaporated to ayellow oil. The crude amide product,4-trifluoromethyl-N-[2-(dimethylamino)cycloopentyl]propionanilide ispurified by formation of the hydrochloride salt and recrystallizationfrom methanol-ether; 3.20 g. (80 %), mp 184°-5°; uv (EtOH): λ_(max) (ε)end absorption, 231 (sh, 2950), 255 (sh, 1100), 262 (881), 268 (627) nm;IR:N⁺ H 2560, 2460, C═C 1660, C═C 1615, 1585, 1520, CF₃ /other 1325,1320, 1175, 1140, 1115, 1075 cm⁻¹ ; mass spectrum: M⁺ 328 (free base);nmr (D₂ O): δ7.9 (m, 4H, aromatic), 2.9 (s, 6H, ⁺ (CH₃)₂ ), 1.4- 2.3 (m,8H, ring hydrogens and CH₃ CH₂ CO), 0.9 (t, 3H, CH₃ CH.sub. 2 CO), otherprotons not observed due to broadening.

Anal. Calcd. for C₁₇ H₂₃ F₃ N₂ O·HCl: Calcd: C, 55.96; H, 6.63; Cl,9.72; F, 15.62; N, 7.68. Found: C, 55.97; H, 6.85; Cl, 9.72; F, 15.48;N, 7.60.

The following Table III summarizes the physical and analytical data forsome additional compounds of this invention, and indicates the procedure(A-via alkanoic acid anhydride, or B-via alkanoyl halide) by which thecompound is made.

                                      TABLE III                                   __________________________________________________________________________    trans-N-(2-aminocyclopentyl)-propionanilides                                   ##STR26##                                                                         Starting     Procedure                                                   Example                                                                            material from                                                                              used                   mp(°C.)                                                                        Analysis                     No.  Table II     A or B                                                                              Y/Z   NR.sub.1 R.sub.2                                                                         (see footnotes)                                                                       Calcd. Found                 __________________________________________________________________________    3    A            A-1   H     N(CH.sub.3).sub.2                                                                        115°-116°.sup.8,a                                                       C, 62.55;                                                                            C, 62.31;                                                              H,  7.53;                                                                            H,  7.43;                                                              N,  6.34;                                                                            N,  6.32                                                               S,  7.24;                                                                            S,  7.17              4    B            B-1   2-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                        129°-130°.sup.6,a                                                       C, 62.62;                                                                            C, 62.82;                                                              H,  7.74;                                                                            H,  7.86;                                                              N,  7.69                                                                             N,  7.57              5    C            A-1   3-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                        139°-40°.sup.6,a                                                        C, 62.62;                                                                            C, 62.32;                                                              H,  7.74;                                                                            H,  7.78;                                                              N,  7.69                                                                             N,  7.66              6    D            A-1   4-CH.sub.3                                                                          N(CH.sub.3).sub.2                                                                        167°-8°.sup.7,a                                                         C, 65.96;                                                                            C, 66.25;                                                              H,  7.18;                                                                            H,  7.03;                                                              N,  5.70;                                                                            N,  5.69;                                                              S,  6.52                                                                             S,  6.56              7    E            B-1   2-Cl  N(CH.sub.3).sub.2                                                                        156°7°.sup.6,a                                                          C, 56.17;                                                                            C, 56.09;                                                              H,  6.55;                                                                            H,  6.59;                                                              Cl,                                                                               9.21;                                                                            Cl,                                                                               9.27;                                                              N,  7.28                                                                             N,  7.24              8    F            A-1   3-Cl  N(CH.sub.3).sub.2                                                                        152°-3°.sup.6,a                                                         C, 56.17;                                                                            C, 55.96;                                                              H,  6.55;                                                                            H,  6.60;                                                              Cl,                                                                               9.21;                                                                            Cl,                                                                               9.12;                                                              N,  7.28                                                                             N,   7.14             9    G            A-1   4-Cl  N(CH.sub.3).sub.2                                                                        75°-6°.sup.1,c                                                          C, 65.18;                                                                            C, 12.09;                                                              H,  7.86;                                                                            H,  7.86;                                                              Cl,                                                                              12.03;                                                                            Cl,                                                                              12.09;                                                              N,  9.50                                                                             N,  9.42              10   H            A-1   3-OCH.sub.3                                                                         N(CH.sub.3).sub.2                                                                        135°-6°.sup.6,a                                                         C, 59.07;                                                                            C, 58.98;                                                              H,  7.63;                                                                            H,  7.60;                                                              N,  7.07                                                                             N,  7.17              11   J            A-1   4-OCH.sub.3                                                                         N(CH.sub.3).sub.2                                                                        146°-8°.sup.7,a                                                         C, 65.03;                                                                            C, 64.68;                                                              H,  6.87;                                                                            H,  7.06;                                                              N,  5.62;                                                                            N,  5.70;                                                              S,  6.43                                                                             S,  6.36              12   K            A-1   3-F   N(CH.sub.3).sub.2                                                                        85°-8°.sup.6,b                                                          C, 58.02                                                                             C, 57.97;                                                              H,  6.96;                                                                            H,  6.89;                                                              F,  5.10;                                                                            F,  5.10;                                                              N,  7.29                                                                             N,   7.51             13   L            A-1   4-F   N(CH.sub.3).sub.2                                                                        154°-5°.sup.7,a                                                         C, 64.17;                                                                            C, 63.93                                                               H,  6.42;                                                                            H,  6.65;                                                              F,  3.90;                                                                            F,  3.76;                                                              N,  5.76;                                                                            N,  5.69;                                                              S,  6.59                                                                             S,  6.83              14   M            A-1   3-Br  N(CH.sub.3).sub.2                                                                        167°-8°.sup.6,a                                                         C, 50.35;                                                                            C, 50.37;                                                              H,  5.87;                                                                            H,  6.01;                                                              Br,                                                                              18.62;                                                                            Br,                                                                              18.37;                                                              N,  6.53                                                                             N,  6.54              15   N            A-1   4-Br  N(CH.sub.3).sub.2                                                                        78°-9°.sup.1,c                                                          C, 56.64;                                                                            C, 56.85;                                                              H,  6.83;                                                                            H,  7.01;                                                              Br,                                                                              23.56;                                                                            Br,                                                                              23.39;                                                              N,  8.26                                                                             N,  8.10              16   P            A-1   4-CH.sub.2 CH.sub.3                                                                 N(CH.sub.3).sub.2                                                                        154°-6°.sup.7,a                                                         C, 67.71;                                                                            C, 67.40;                                                              H,  7.31;                                                                            H,  7.53;                                                              N,  5.64;                                                                            N,  5.55;                                                              S,  6.46                                                                             S,  6.64              17   R            A-1   3,4-Di-                                                                             N(CH.sub.3).sub.2                                                                        154°-5°.sup.4,a                                                         C, 53.94;                                                                            C, 53.91;                                     Cl                       H,  5.89;                                                                            H,  5.82;                                                              Cl,                                                                              15.92;                                                                            Cl,                                                                              15.82;                                                              N,  6.29                                                                             N,  6.33              18   S            B-1   3,5-  N(CH.sub.3).sub.2                                                                        129°-30°.sup.4,a                                                        C, 53.94;                                                                            C, 53.46;                                     DiCl                     H,  5.89;                                                                            H,  6.04;                                                              Cl,                                                                              15.92;                                                                            Cl,                                                                              15.78;                                                              N,  6.29                                                                             N,  6.52              19   T            A-1   3,4-di-                                                                             N(CH.sub.3).sub.2                                                                        155°-6°.sup.5,a                                                         C, 60.53;                                                                            C, 60.47;                                     OCH.sub.3                H,  7.39;                                                                            H,  7.38;                                                              N,  6.42                                                                             N,  6.67              20   U            B-1   3-CF.sub.3                                                                          N(CH.sub.3).sub.2                                                                        135°-6°.sup.6,a                                                         C, 54.54;                                                                            C, 54.50;                                                              H,  6.02;                                                                            H,  6.21;                                                              F, 13.62;                                                                            F, 14.09;                                                              N,  6.70                                                                             N,  6.45              21   V            B-1   4-CF.sub.3                                                                          N(CH.sub.3).sub.2                                                                        184°-5°.sup.2,a                                                         C, 55.96;                                                                            C, 55.97;                                                              H,  6.63;                                                                            H,  6.85;                                                              Cl,                                                                               9.72;                                                                            Cl,                                                                               9.72;                                                              F, 15.62;                                                                            F, 15.48;                                                              N,  7.68                                                                             N,  7.60              22   W            B-1   3-Cl, N(CH.sub.3).sub.2                                                                        122°-3°.sup.6,a                                                         C, 57.21;                                                                            C, 57.20;                                     4-Me                     H,  6.82;                                                                            H,  6.84;                                                              Cl,                                                                               8.89;                                                                            Cl,                                                                               8.84;                                                              N,  7.02                                                                             N,  6.78              23   AA           B-1   4-Cl, N(CH.sub.3).sub.2                                                                        131°-2°.sup.6,a                                                         C, 57.21;                                                                            C, 57.09;                                     3-Me                     H,  6.82;                                                                            H,  6.93;                                                              Cl,                                                                               8.89;                                                                            Cl,                                                                               9.02;                                                              N,  7.02                                                                             N,  6.99              24   CC           A-1   3,4-  N(CH.sub.2 CH.sub.3).sub.2                                                               148° -9°.sup.9,a                                                        C, 50.33;                                                                            C, 50.15;                                     diCl                     H,  6.67;                                                                            H,  6.80;                                                              Cl,                                                                              15.64;                                                                            Cl,                                                                              15.82;                                                              N,  6.18;                                                                            N,  6.06;                                                              S,  7.07                                                                             S,  6.96              25   DD           A-1   3,4- diCl                                                                            ##STR27## 107°-9°.sup.6,a                                                         C, H, Cl, N,                                                                     52.86;  5.99; 15.61;                                                          .16 C, H, Cl,                                                                        53.08;  6.01;                                                                 15.73;  6.00       26   GG           B-1   3,4- diCl                                                                            ##STR28## 165°-6°.sup.2,a                                                         C, H, Cl, N,                                                                     47.81;  6.97; 29.72;                                                          .80 C, H, Cl,                                                                        47.52;  6.64;                                                                 29.98;  8.86       27   HH           B-1   3,4- diCl                                                                            ##STR29## 259°-60°                                                                C, H Cl, N,                                                                      50.27;  7.07; 29.68;                                                          .79 C, H, Cl,                                                                        50.30;  6.99;                                                                 29.57;  8.52       28   R            A-1   3-Cl, N(CH.sub.3).sub.2                                                                        152°-3°                                                                 C,up.6,a                                                                         53.66;                                                                            C, 53.52;                                     4-F                      H,  6.00;                                                                            H,  6.13;                                                              N,  6.96;                                                                            N,  6.88;                                                              Cl,                                                                               8.80;                                                                            Cl,                                                                               8.65;                                                              C,  4.72                                                                             F,  4.96              29   R            A-1   3,4-  N(CH.sub.3).sub.2                                                                        146°-7°                                                                 C,up.6,a                                                                         42.54;                                                                            C, 42.66;                                     diBr                     H,  4.76;                                                                            H,  4.90;                                                              N,  5.51;                                                                            N,  5.71;                                                              Br,                                                                              31.45                                                                             Br,                                                                              31.51              30   R            A-1   3,4-  N(CH.sub.3).sub.2                                                                        114°-5°                                                                 C,up.6,a                                                                         62.72;                                                                            C, 62.60;                                     diCH.sub.3               H,  8.03;                                                                            H,  8.14;                                                              N,  7.32                                                                             N,  7.31              31   FF           A-1   3,4-  N(CH.sub.3)CH.sub.2                                                                      104°-6°                                                                 C,up.6,a                                                                         53.94;                                                                            C, 54.14;                                     diCl  CHCH.sub.2         H,  5.87;                                                                            H,  5.88;                                                              N,  6.29;                                                                            N,  6.47;                                                              Cl,                                                                              15.92                                                                             Cl,                                                                              15.91              32   EE           A-1   3,4-  N(CH.sub.3)CH.sub.2                                                                      120°-1°                                                                 C,up.6,a                                                                         56.14;                                                                            C, 56.10;                                     diCl  C.sub.6 H.sub.5    H,  5.89;                                                                            H,  5.49;                                                              N,  5.46;                                                                            N,  5.25                                                               Cl,                                                                              13.81                                                                             Cl,                                                                              13.26              33                                                                                  ##STR30##   A-1   3,4- diCl                                                                            ##STR31## 90°-1°                                                                  C, H, N, Cl,                                                                     57.67;  6.32;  5.17;                                                          13.09                                                                             C, 57.52  6.23;                                                                  4.98; 12.62        34                                                                                  ##STR32##   A-1   3,4-  diCl                                                                          N(CH.sub.2 CH.sub.2 CH.sub.3).sub.2                                                      58°-9°                                                                  C, H, N, Cl,                                                                     62,33;  7.85;  7.27;                                                          18.40                                                                             C, H, N, Cl,                                                                     62.64;  8.02;                                                                 .41; 18.27         35   R            A-1   3,4- diCl                                                                            ##STR33## 131°(decomp)                                                                   C, H, N, Cl,                                                                     55.65;  6.42;  8.12;                                                          20.54                                                                             C, H, N, Cl,                                                                     51.19;  6.32;                                                                 .22; 22.76         36   *** --       A-1   H                                                                                    ##STR34## 169°-70°                                                                C, H, N, Cl,                                                                     63.45;  8.54;  9.25;                                                          11.70                                                                             C, H, N, Cl,                                                                     63.51;  8.61;                                                                 .33; 11.90         37   see text     A-1   3-Cl 4-Cl                                                                            ##STR35## 171°-3°                                                                 C, H, N, Cl,                                                                     51.56;  5.77;  6.68;                                                          16.91                                                                             C, H, N, Cl,                                                                     51.84;  5.85;                                                                 .66;               __________________________________________________________________________                                                               17.11              Derivative  Recrystallization solvent                                                                 Procedure A                                           __________________________________________________________________________    .sup.1 free base                                                                          .sup.a methanol-ether                                                                     .sup.1 propionic anhydride                            .sup.2 hydrochloride                                                                      .sup.b ethanol-ether                                                                      .sup.2 acetic anhydride                               .sup.3 hydrobromide                                                                       .sup.c petroleum ether                                                                    .sup.3 butyric anhydride                              .sup.4 maleate                                                                            .sup.d ether                                                                              Procedure B                                           .sup.5 fumarate                                                                           .sup.e petroleum ether-ether                                                              .sup.1 propionyl chloride                             .sup.6 oxalate                                                                            .sup.f benzene                                                                            .sup.2 cyclopropanecarbonyl chloride                  .sup.7 2-naphthalenesulfonate                                                             .sup.g dioxane                                                                            .sup.3 acryloyl chloride                              .sup.8 p-toluenesulfonate                                                                             .sup.4 cyclobutanecarbonyl chloride                   .sup.9 methanesulfonate .sup.5 cyclohexanecarbonyl chloride                                           .sup.6 isobutynyl chloride                                                    .sup.7 ethylchloroformate                                                     .sup.8 methoxyacetyl chloride                          *Prepared in manner similar to other diamines of Table II.                    **cis configuration                                                           ***Follow procedures of Example 37 (text) but substitute equivalent amoun     of aniline for 3,4-dichloroaniline.                                      

                                      TABLE IV                                    __________________________________________________________________________    trans-N-(2-aminocyclopentyl)anilides; Miscellaneous                            ##STR36##                                                                    Starting                                                                      material from                 mp(°C.)/                                                                              Analysis                         Example                                                                            Table II                                                                             Y/Z                                                                              Procedure                                                                           Q R      see footnote                                                                         Formula Calcd.                                                                              Found                      __________________________________________________________________________    38   A      H  A-2   O CH.sub.3                                                                             104°.sup.1,e                                                                  C.sub.15 H.sub.22 N.sub.2 O                                                           C,                                                                              73.13;                                                                            C,                                                                              73.21;                                                                H,                                                                               9.00;                                                                            H,                                                                              8.96;                                                                 N,                                                                              11.37                                                                             N,                                                                              11.23                    39   A      H  A-3   O                                                                                ##STR37##                                                                           115°-16°.sup.7,a                                                       C.sub.17 H.sub.26 N.sub.2 O .                                                 C.sub.10 H.sub.9 SO.sub.3 . 1/4                                               H.sub.2 O                                                                             C, H, N, S,                                                                     66.57;  7.14;  5.75;                                                              C, H, N, S,                                                                     66.42;  7.13;  5.70;                                                           6.48                    40   R      3,4-                                                                             A-2   O CH.sub.3                                                                             164°-5°.sup.6,a                                                        C.sub.15 H.sub.20 Cl.sub.2 -                                                          C,                                                                              50.38;                                                                            C,                                                                              50.28;                               diCl                     N.sub.2 O . C.sub.2 H.sub.3 O.sub.4                                                   H,                                                                               5.47;                                                                            H,                                                                               5.54;                                                                N,                                                                               6.91;                                                                            N,                                                                               6.79;                                                                Cl,                                                                             17.50                                                                             Cl,                                                                             17.29                    41   R      3,4- diCl                                                                        A-3   O                                                                                ##STR38##                                                                           120°-1°.sup.6,a                                                        C.sub.17 H.sub.24 Cl.sub.2 - N.sub.2                                          O . C.sub.2 H.sub.2 - O.sub.9                                                         C, H, N, Cl,                                                                    52.66;  6.05;  6.47;                                                              C, H, N, Cl,                                                                    52.84;  6.16;  6.69;                                                          6.47                     42   R      3,4- diCl                                                                        B-2   O                                                                                ##STR39##                                                                           145°-6°.sup.6,a                                                        C.sub.17 H.sub.22 Cl.sub.2 N.sub.2 O                                          . C.sub.2 H.sub.2 O.sub.4 . 1/2                                               H.sub.2 O                                                                             C, H, N, Cl,                                                                    51.82;  5.72;  6.36;                                                              C, H, N, Cl,                                                                    51.38;  5.62;  6.36;                                                          6.11                     43   R      3,4- diCl                                                                        B-4   O                                                                                ##STR40##                                                                           101°-3°.sup.6,a                                                        C.sub.18 H.sub.24 Cl.sub.2 N.sub.2 O                                          . 1/4 Et.sub.2 O                                                                      C, H N, Cl,                                                                     54.77;  6.48;  5.81;                                                              C, H, N, Cl,                                                                    54.28;  6.38;  5.70;                                                          4.98                     44   R      3,4- diCl                                                                        B-5   O                                                                                ##STR41##                                                                           118°-9°.sup.1,c                                                        C.sub.20 H.sub.28 Cl.sub.2 N.sub.2                                                    C, H, N, Cl,                                                                    62.66;  7.36;  7.31;                                                              C, H, N, Cl,                                                                    62.94;  7.50;  7.31;                                                          8.59                     45   R      3,4-                                                                             B-3   O CHCH.sub.2                                                                           196°-7°.sup.6,a                                                        C.sub.16 H.sub.20 Cl.sub.2 N.sub.2 O                                          .       C,                                                                              51.25;                                                                            C,                                                                              51.31;                               diCl                     C.sub.2 H.sub.2 O.sub.4 . 1/2                                                 H.sub.2 O                                                                             H,                                                                               5.37;                                                                            H,                                                                               5.39;                                                                N,                                                                               6.64;                                                                            N,                                                                               6.61;                                                                Cl,                                                                             16.81                                                                             Cl,                                                                             16.70                    46   R      3,4-                                                                             B-6   O CH(CH.sub.3).sub.2                                                                   171°-4°.sup.6,a                                                        C.sub.17 H.sub.24 Cl.sub.2 N.sub.2 O                                          .       C,                                                                              52.66;                                                                            C,                                                                              52.65;                               diCl                     C.sub.2 H.sub.2 O.sub.4                                                               H,                                                                               6.05;                                                                            H,                                                                               6.15;                                                                N,                                                                               6.47;                                                                            N,                                                                               6.50;                                                                Cl,                                                                             16.36                                                                             Cl,                                                                             16.26                    47   R      3,4-                                                                             A-1   S CH.sub.2 CH.sub.3                                                                    192°-4°.sup.6,a                                                        C.sub.18 H.sub.22 Cl.sub.2 N.sub.2 S                                          .       C,                                                                              49.65;                                                                            C,                                                                              49.74;                               diCl                     C.sub.2 H.sub.2 O.sub.4                                                               H,                                                                               5.56;                                                                            H,                                                                               5.71;                                                                N,                                                                               6.44;                                                                            N,                                                                               6.40;                                                                Cl,                                                                             16.29;                                                                            Cl,                                                                             16.46;                                                                S,                                                                               7.37                                                                             S,                                                                               7.31                    48   R      3,4-                                                                             B-7   O OCH.sub.2CH.sub.3                                                                    121°-2°.sup.6,a                                                        C.sub.16 H.sub.22 Cl.sub.2 -                                                          C,                                                                              49.66;                                                                            C,                                                                              49.69;                               diCl                     N.sub.2 O.sub.2 . C.sub.2 H.sub.2                                             O.sub.4 H,                                                                               5.56;                                                                            H,                                                                               5.74;                                                                N,                                                                               6.44;                                                                            N,                                                                               6.77;                                                                Cl,                                                                             16.29                                                                             Cl,                                                                             16.30                    49   R      3,4 diCl                                                                         B-8   O                                                                                ##STR42##                                                                           132°-3°.sup.6,a                                                        C.sub.16 H.sub.22 Cl.sub.2 - N.sub.2                                          O.sub.2 . C.sub.2 H.sub.2 O.sub.4                                                     C, H, N, Cl,                                                                    49.66;  5.56;  6.44;                                                              C, H, N, Cl,                                                                    49.94;  5.53;  6.44;                                                          6.40                     __________________________________________________________________________    Derivative  Recrystallization solvent                                                                 Procedure A                                           __________________________________________________________________________    .sup.1 free base                                                                          .sup.a methanol-ether                                                                     .sup.1 propionic anhydride                            .sup.2 hydrochloride                                                                      .sup.b ethanol-ether                                                                      .sup.2 acetic anhydride                               .sup.3 hydrobromide                                                                       .sup.c petroleum ether                                                                    .sup.3 butyric anhydride                              .sup.4 maleate                                                                            .sup.d ether                                                                              Procedure B                                           .sup.5 fumarate                                                                           .sup.e petroleum ether-ether                                                              .sup.1 propionyl chloride                             .sup.6 oxalate                                                                            .sup.f benzene                                                                            .sup.2 cyclopropanecarbonyl chloride                  .sup.7 2-naphthalenesulfonate                                                             .sup.g dioxane                                                                            .sup.3 acryloyl chloride                              .sup.8 p-toluenesulfonate                                                                             .sup.4 cyclobutanecarbonyl chloride                   .sup.9 methanesulfonate .sup.5 cyclohexanecarbonyl chloride                                           .sup.6 isobutynyl chloride                                                    .sup.7 ethylchloroformate                                                     .sup.8 methoxyacetyl chloride                         __________________________________________________________________________     *Prepared in manner similar to other diamines of Table II.                    **cis configuration                                                           ***Follow procedures of Example 37 (text) but substitute equivalent amoun     of aniline for 3,4-dichloroaniline.                                      

EXAMPLE 35 Preparation of trans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide-2-N-oxide

Three and five-hundredths grams (0.015 mol) of 85% m-chloroperbenzoicacid in 50 ml. of CHCl₃ is added dropwise over 30 min. to 3.29 g. (0.01mol) oftrans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide,(prepared in Ex. 1), with ice cooling; the mixture is stirred overnightat room temperature, and is then evaporated to dryness. A viscous oil isobtained; this oil is treated with 50 ml. of ether, and a two-phasesystem results. This mixture is filtered through 100 g. of silica gel(sintered glass funnel), and eluted with 1500 ml. of ether followed by500 ml. of MeOH. The MeOH is evaporated to give a residue which isdissolved in warm dioxane, filtered to remove foreign matter, anddiluted with ether to the point of cloudiness. Crystals form, and theseare recrystallized from dioxane/ether at room temperature. The yield is0.25 g. (7% yield). NMR (CDCl₃) and IR are consistent with titlecompound. Analysis and m.p. are in Table IV.

EXAMPLE 37 Preparation of cis-3,4-dichloro-N-[2(dimethylamino)cyclopentyl]propionanilide

Part (A) A solution of 3,4-dichloroaniline (200 g., 1.23 mol),cyclopentene oxide (400 ml.), and conc. HCl (2 ml.) is heated at refluxtemperature for 7 days. The unreacted epoxide is evaporated at 60°, andthe residue is treated with excess ethereal HCl, and a syrup results.This is washed with 1000 ml. of ether. The residue is crystallized andrecrystallized from methanol/ether, (1/5.5, v/v) to give 170.0 g. (49% vyield) of 3,4-dichloro-N-[2-hydroxycyclopentyl]aniline, hydrochloridesalt.

Part (B) Propionic anhydride (208 g., 1.6 mol), and the free-base frompart (A) (113.2 g., 0.40 mol base) are mixed and heated on a steambathovernight. Water (350 ml.) is added, and heating is continued for 1 hr.After ice cooling, the reaction mixture is neutralized with 240 ml. of40% NaOH (2.4 mol), and extracted with ether. The ether extract iswashed in succession with saturated NaHCO₃, water, 10% HCl, water andsaturated NaCl, the organic layer dried over MgSO₄, and then evaporatedto a brown oil. Subsequently, this oil is dissolved in 500 ml. 95% EtOH,and 26.4 g. (0.4 mol) of 85% KOH is added. The solution is stirred atroom temperature (slight warming) for 3 hr. Evaporation removes theEtOH. The residue is treated with 800 ml. of ether and 250 ml. of water.The organic layer is washed successively with water, 10% HCl, andsaturated NaCl, and dried (MgSO₄). The solution is concentrated bydistillation and subsequent treatment with petroleum ether results in87.7 g. (72% yield) of3,4-dichloro-N-[2-hydroxycyclopentyl]propionanilide.

Part (C) To an ice-cooled solution of 60.4 g. (0.20 mol) of Part (B)product in 1000 ml. of acetone there is added, dropwise, 75 ml. of JonesReagent (oxidizing). The reaction mixture is stirred at room temperaturefor 30 min., then is filtered, and the filtrate concentrated at reducedpressure. The residue is dissolved in 500 ml. of ether and this solutionis washed three times with water followed by saturated NaCl solution, isdried over MgSO₄ and evaporated to a yellow oil which solidifies onstanding. A tacky solid results (44.4 g, 74% yield) which is3,4-dichloro-N-[2-oxocyclopentyl]propionanilide.

Part (D) A solution of dimethylamine (0.24 mol) and dimethylaminehydrochloride (9.8 g., 0.12 mol) in 250 ml. MeOH is prepared, and 18.0g. (0.06 mol) of the ketone (from Part (C)) is added all at once. Tothis mixture is added all at once, 2.65 g. (0.042 mol) of sodiumcyanoborohydride and 3A molecular sieves (25 g.). The entire mixture isstirred at room temperature for 8 days, after which time the solution istreated with 10% HCl until gas evolution ceases. Filtration through afilter aid (Celite®) removes the sieves and a small amount of insolublematter. The MeOH is evaporated and the remaining aqueous layer, afterwashing with ether, is made basic with 50 ml. of 40% NaOH, and isfiltered to remove amorphous solid. The residue is washed with ether,and the filtrate is extracted with ether. The ether extracts are washedwith saturated NaCl solution, dried (MgSO₄) and evaporated to ayellow-brown oil (6.1 g.). Chromatography on 150 g. silica gel (2% MeOHin CHCl₃) gives several 20 -ml. fractions; fractions 11- 33 (homogeneousby TLC) are combined and evaporated to give 4.2 g. of yellow oil whichis converted to the oxalic acid salt in MeOH/ether (1/5, v/v). A solidresults (11% yld.), which has a m.p. 171°-3°. This solid is thecis-3,4-dichloro-N[2-(dimethylamino)cyclopentyl]-propionanilide oxalicacid salt. The nmr differs from that of the trans compound (Example 1)in the coupling constant of the 1,2-cyclopentane H's. Also, on TLC onsilica gel (EtOAc developing solvent), the free base from this reaction(cis) has a different R_(f) value than the corresponding transaminoamide.

Anal. Calcd. for C₁₆ H₂₂ N₂ Cl₂ O·C₂ H₂ O₁ : Calcd.: C, 51.56; H, 5.77;N, 6.68; Cl, 16.91. Found: C, 51.84; H, 5.85; N, 6.66; Cl, 17.11.

EXAMPLE 50 Preparation of d- and l-trans-trans-3,4-dichloro-N-[2-dimethylaminocyclopentyl]aniline.

(l-isomer) The di-p-toluoyl-d-tartaric acid salt of the titletrans-dl-diamine is prepared by mixing 103.9 g. (0.267 mol) of thistartaric acid with 103.2 g. (0.267 mol) the diamine in a solventconsisting of 500 ml. isopropanol and about 500 ml. of ether. Thismixture is seeded with a crystal of the trans-1-diamine, obtained from asmall test tube scale resolution preparation, and left to stand.Crystals form; these are collected (75.0 g.) by filtration andrecrystallized twice from a mixture of methanol:acetone:ether: 2:8:7.5v/v/v to give 17.5 g. of salt which is converted to the free base withaqueous 20% NaOH, and subsequently to the maleate salt (as in Example1). Mother liquor saved. Nmr, ir, and mass spectra conform to theassigned structure. m.p. 135°- 6°; [α]_(D) ²⁵ (MeOH, c.=15.47 mg/2 ml)=-105° to give the l-form of the compound.

Analysis Calcd. for C₁₃ H₁₈ N₂ Cl₂ ·C₁ H₁ O₄ : Calcd.: C, 52.45; H,5.70; N, 7.20; Cl, 18.22. Found: C, 52.71; H, 5.76; N, 7.19; Cl, 18.23.

d-isomer The mother liquor from the initial filtration (above) isconcentrated under reduced pressure to give a yellow oil whichcrystallizes in a solvent mixture of MeOH-acetone-ether to give 76.0 g.of crystals; these are then recrystallized twice frommethanol-acetone-ether to give 55.0 g. of crystalline material which isconverted to the free base and subsequently to the maleic acid additionsalt. Spectral data are correct for the assigned structure. m.p. 135°-6°; [α]_(D) ²⁵ (MeOH, c.= 15.63 mg./2 ml.)= +101° (i.e. the d-isomer).

Anal. Calcd. for C₁₃ H₁₈ N₂ Cl₂ ·C₄ H₄ O₄ : Calcd.: C, 52.45; H, 5.70;N, 7.20; Cl, 18.22. Found: C, 52.73; H, 5.80; N, 7.28; Cl, 18.47.

EXAMPLE 51 Preparation ofd-trans-3,4-dichloro-N-[2-dimethylaminocyclopentane]propionanilide

Following the procedure of Example 1, but substitutingd-trans-aminoaniline (prepared in Example 50), for thetrans-aminoaniline of Example 1 as starting diamine there is obtainedthe titled compound as the maleic acid addition salt, m.p. 152°- 4°.Circular Dichroism [θ]₂₄₉μ ²⁵° +2800± 300 (2.5% in 95% EtOH).

Anal. Calcd. for C₁₆ H₂₂ N₂ Cl₂ ·C₄ H₄ O₄ : Calcd.: C, 53.94; H, 5.89;N, 6.29; Cl, 15.92. Found: C, 54.19; H, 5.91; N, 6.19; Cl, 16.22.[θ]=molecular ellipticity

Preparation ofl-trans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide.

Following the procedure of Example 1 but substitutingl-trans-aminoaniline (prepared in Example 50 ) for thetrans-aminoaniline in Example 1, as starting diamine there is obtainedthe titled compound as the maleic acid addition salt, m.p. 152°- 4°.Circular Dichroism [θ]₂₄₉μ²⁵° -2900±300(2.5% in 95% EtOH).

Anal. Calcd. for C₁₆ H₂₂ N₂ Cl₂ O·C₄ H₄ O₄ : Calcd.: C, 53.94; H, 5.89;N, 6.29; Cl, 15.92. Found: C, 54.09; H, 5.90; N, 6.54; Cl, 15.82.

EXAMPLE 47 Preparation oftrans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]thiopropionanilide.

A solution of 8.23 g. (0.025 mol) of 3',4'-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide, (prepared inExample 1) and phosphorus pentasulfide (6.1 g., 0.028 mol) in 250 ml. ofpyridine is heated at the reflux temperature overnight. The pyridine isthen removed by distillation at ca 100°, in vacuo. The residue istreated with 250 ml. CHCl₃ and 200 ml. saturated aqueous sodiumbicarbonate and stirred for 1 hr. The organic layer is diluted with 250ml. of ether and washed successively with 200 ml. of water and 250 ml.of saturated NaCl solution, dried (anhy. MgSO₄), and evaporated to ared-brown oil. This oil is triturated twice with hot petroleum ether; ayellow solution and a red solid result. The yellow solution is washedwith water, dried (MgSO₄), and evaporated to a pale orange oil (3.7 g.,43% yield). The oxalic acid salt is prepared with the oil and 1.0 g.(0.011 mol) of acid in 25 ml. MeOH and 200 ml. ether. Onrecrystallization, 3.6 g. (33% yield) of the oxalic acid addition saltof the title compound is prepared (see Table IV, Example 47, foranalysis and m.p.) Nmr correct for assigned structure.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula I is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Wafers are prepared in the same manner as tablets, differing only inshape and the inclusion of sucrose or other sweetener and flavor. Intheir simplest embodiment, capsules, like tablets, are prepared bymixing the compound with an inert pharmaceutical diluent and filling themixture into a hard gelatin capsule of appropriate size. Soft gelatincapsules are prepared by machine encapsulation of a slurry of thecompound with an acceptable vegetable oil, light liquid petrolatum, orother inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydro-alcoholic (ethanol) vehicle with suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Rectal suppositories as used herein mean solid bodies for insertion intothe rectum which melt or soften at body temperature releasing one ormore pharmacologically or therapeutically active ingredients.

Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point.

Examples of bases or vehicles include, for example, cocoa butter(theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol)and appropriate mixtures of mono-, di-, and triglycerides of fattyacids. Combinations of the various bases may be used. Agents to raisethe melting point of suppositories include, for example, spermaceti andwax. Rectal suppositories may be prepared either by the compressedmethod or by molding. The usual weight of a rectal suppository is about2.0 gm.

Tablets and capsules for rectal administration are manufacturedutilizing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Rectal suppositories, tablets or capsules are packaged eitherindividually, in unit-dose, or in quantity, multiple dose, for example,2, 6, or 12.

The term unit dosage form, as used in the specification and claims,refers to physically discrete units suitable as unitary dosages formammals including human subjects each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier, or vehicle. The specifications for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved, and (b) the limitations inherent in the art ofcompounding such an active material for use in humans, as disclosed indetail in this specification, these being features of the presentinvention. Examples of suitable unit dosage forms in accord with thisinvention are tablets, capsules, pills, suppositories, powder packets,granules, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls,ampuls, vials, segregated multiples of any of of the foregoing, andother forms as herein described.

The dosage of the compound for treatment depends on route ofadministration, the age, weight and condition of the patient. A dosageschedule of from about 1 to about 100 mg., preferably 10 to 90 mg. perday, given in a single dose or in subdivided doses, embraces theeffective range to alleviate depression for which the compositions areeffective. The dosage to be administered is calculated on the basis offrom about 0.02 to about 1.5 mg./kg. of weight of the subject. Thecompound is compounded with a suitable pharmaceutical carrier in unitdosage form for convenient and effective administration. In thepreferred embodiments of this invention, the dosage units can containthe compound in 0.5, 1, 5, 10, 20, 30, 50 and 100 mg. amounts forsystemic treatment. A sterile preparation of the active materialcontains 0.1 percent to 25 percent w/v for parenteral treatment. Thedosage of compositions containing a compound of formula I and one ormore other active ingredients is to be determined with reference to theactual dosage of each such ingredient.

In addition to the administration of a compound of formula I as theprincipal active ingredient of compositions for treatment of theconditions desired herein, the said compound can be combined with othercompounds such as analgesics, for example, aspirin, acetaminophen, PACcompound (phenacetin-aspirin-caffeine), antiinflammatory agents such asibuprofen, and the like, anxiolytics such as perphenazine, amitriptylenehydrochloride, chlordiazepoxide, alprazolam, doxepin hydrochloride, andthe like.

EXAMPLE 52

A lot of 10,000 tablets, each containing 20 mg. oftrans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilidemaleate salt, as the active ingredient compound is prepared from thefollowing types and amounts of ingredients:

    ______________________________________                                        Active ingredient compound                                                                             200 gm.                                              Dicalcium phospate       1,500 gm.                                            Methylcellulose, U.S.P. (15 cps.)                                                                      60 gm.                                               Talc                     150 gm.                                              Corn Starch              200 gm.                                              Magnesium stearate       12 gm.                                               ______________________________________                                    

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in reducing depression in adults at a dose of 1to 2 tablets per day, depending on the age and weight of the patient.

EXAMPLE 53

One thousand two-piece hard gelatin capsules each containing 10 mg. of3-bromo-N-[2-(dimethylamino)cyclopentyl]propionanilide, hydrochloridesalt as the active ingredient compound are prepared from the followingtypes and amounts of ingredients:

    ______________________________________                                        Active ingredient compound                                                                            10 gm.                                                Lactose                 75 gm.                                                Talc                    25 gm.                                                Magnesium stearate       1.5 gm.                                              ______________________________________                                    

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful for treating depression in adults at adose of one-two capsules per day.

EXAMPLE 54

One thousand tablets for sublingual use are prepared from the followingingredients:

    ______________________________________                                        3-trifluoromethyl-N-[2-(dimethylamino)cyclopentyl]-                            propionanilide, micronized 5 gm.                                             Polyethylene glycol 4,000, powdered                                                                       150 gm.                                           Polyethylene glycol 6,000, powdered                                                                       75 gm.                                            ______________________________________                                    

The ingredients are mixed well and compressed into sublingual-typetablets.

These tablets (each containing 5 mg. of active ingredient) placed underthe tongue are useful to reduce depression with a rapid reduction at adose of 1 tablet per 6 hours.

EXAMPLE 55

Soft gelatin capsules for oral use, each containing 10 mg. of3,4-dichloro-N-[2-(diethylamino)cyclopentyl]-propionanilide,methanesulfonate salt are prepared by first dispersing the micronizedcompound in corn oil to render the material capsulatable and thenencapsulating in the usual manner. These capsules are useful intreatment of depression at a dose of 1- 2 capsules a day.

EXAMPLE 56

One thousand tablets, each containing 30 mg. of3,4-dichloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, salt aremade from the following types and amounts of ingredients:

    ______________________________________                                        3,4-dichloro-[2-(N-pyrrolidinyl)cyclopentyl]-                                  propionanilide           30 gm.                                              Lactose                   355 gm.                                             Microcrystalline cellulose NF                                                                           120 gm.                                             Starch                    16 gm.                                              Magnesium stearate powder 4 gm.                                               ______________________________________                                    

The ingredients are screened and blended together and pressed intotablets.

The tablets are useful to overcome depression.

EXAMPLE 57

A sterile preparation suitable for intramuscular injection andcontaining 50 mg. of3-fluoro-N-[2-(dimethylamino)cyclopentyl]propionanilide, hydrochloridesalt, in each milliliter is prepared from the following ingredients:

    ______________________________________                                        3-fluoro-N-[2-(dimethylamio)cyclopentyl]-                                      propionanilide, hydrochloride                                                                          50 gm.                                              Benzyl benzoate           200 ml.                                             Methylparaben             1.5 gm.                                             Propylparaben             0.5 gm.                                             Cottonseed oil q.s.       1,000 ml.                                           ______________________________________                                    

One milliliter of this sterile preparation is injected to reducedepression in adults.

EXAMPLE 58

Following the procedure of the preceding Examples 52 through 57,inclusive, unit dosage forms are similarly prepared substitutingequivalent amounts of cis or trans variants of other Formula Icompounds; for example

3-chloro-4-methyl-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[{2-(N-methyl-N-dimethylaminoethyl)amino}cyclopentyl]propionanilide,

3,4-dimethoxy-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-chloro-4-fluoro-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dibromo-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dimethyl-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]cyclopropanecarboxanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]thiopropionanilide,

3,4-dichloro-N-[2-(N-methyl-N-β-phenylethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-methoxy-N-[2-(dimethylamino)cyclopentyl]propionanilide,

3-chloro-4-methyl-N-[2-dimethylaminocyclopentyl]propionanilide,

3,4-dichloro-N-[2-(diethylamino)cyclopentyl]propionanilide,

3,4-dichloro-N-[2-dimethylaminocyclopentyl]cyclohexanecarboxanilide, ortheir pharmacologically acceptable acid addition salts for therespective active ingredients in those examples.

I claim:
 1. A process for treating depression which comprisesadministering to a depressed human a compound of the formula ##STR43##wherein the wavy line (˜) in the 1-position of the cyclopentyl ringindicates cis or trans configuration of the substituents in the 1- and2-positions of the cyclopentyl ring;p is zero or 1; Q is oxygen orsulfur; R is C₁ to C₃ -alkyl R₁ and R₂ are taken together with thenitrogen to which they are bonded they complete an N-pyrrolidinyl orN-piperidinyl ring;each of Y and Z is selected from the group consistingof hydrogen, a halogen having an atomic number of from 9 to 35,trifluoromethyl, C₁ to C₂ -alkyl and C₁ to C₂ -alkyloxy and when Y istrifluoromethyl Z is hydrogen, when Y is C₁ to C₂ -alkyloxy and Z ishydrogen the C₁ to C₂ -alkyloxy is in the 3-position, when Y and Y and Zare both halogens or C₁ to C₂ -alkyloxy they are present in the 3- and4- or 3- and 5-positions, or a pharmacologically acceptable saltthereof, in an amount in the range from about 1 to about 100 mg. perdosage unit to alleviate the conditions of depression, in associationwith a pharmaceutical carrier.
 2. A process according to claim 1 whereinthe formula I compound is one in which R is C₁ to C₃ -alkyl, R₁ and R₂are taken together with the nitrogen to which they are bonded tocomplete an N-pyrrolidinyl or N-piperidinyl moiety, and at least one ofY and Z is a halogen having an atomic number of from 9 to 35, in the 3-or 4-position, or a pharmacologically acceptable salts thereof.
 3. Aprocess according to claim 1 wherein the compound is3,4-dichloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, or apharmacologically acceptable salt thereof.
 4. A pharmaceuticalpreparation in dosage unit form adapted for administration to obtain ananti-depression effect comprising per dosage unit, an anti-depressanteffective, non-toxic amount in the range from about 1 to about 100 mg.of a compound of the formula ##STR44## wherein the wave line (˜) in the1-position of the cyclopentyl ring indicates cis or trans configurationof the substituents in the 1- and 2-positions of the cyclopentyl ring;pis zero or 1; Q is oxygen or sulfur; R is C₁ to C₃ -alkyl; R₁ and R₂ aretaken together with the nitrogen to which they are bonded they completean N-pyrrolidinyl or N-piperidinyl ring; each of Y and Z is selectedfrom the group consisting of hydrogen, a halogen having an atomic numberof from 9 to 35, trifluoromethyl, C₁ to C₂ -alkyl and C₁ to C₂ -alkyloxyand when Y is trifluoromethyl Z is hydrogen, when Y is C₁ to C₂-alkyloxy and Z is hydrogen the C₁ to C₂ -alkyloxy is in the 3-position,when Y and and Z are both halogens or C₁ to C₂ -alkyloxy they arepresent in the 3- and 4- or 3- and 5-positions, or a pharmacologicallyacceptable salt thereof, and a pharmaceutical diluent.
 5. Apharmaceutical preparation according to claim 4 wherein the compound offormula I is in the trans configuration.
 6. A pharmaceutical preparationaccording to claim 5 wherein the compound of formula I is in the cisconfiguration.
 7. A pharmaceutical preparation according to claim 4wherein in the formula I compound R is C₁ to C₃ -alkyl, R₁ and R₂ aretaken together with the nitrogen to which they are bonded to complete anN-pyrrolidinyl or N-piperidinyl moiety, and at least one of Y and Z is ahalogen having an atomic number of from 9 to 35, in the 3- or4-position, or a pharmacologically acceptable salt thereof.
 8. Apharmaceutical preparation according to claim 7 wherein the formula Icompound is3,4-dichloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, or apharmacologically acceptable salt thereof. 9.3,4-Dichloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, and thepharmacologically acceptable salts thereof.